|Therapeutic Strategies for Cognitive Impairment in Fragile X: AMPAkines
by Julie Lauterborn, 6/1/2003
This study complements Dr. Berry-Kravis’s human trial of the Ampakine drug CX516. Dr. Lauterborn aims to understand the actions of newer Ampakine compounds which are not yet tested for human use but which are more potent than CX516.
Fragile X (FX) syndrome and other forms of mental retardation are characterized by abnormalities in the
dendritic spines of cortical pyramidal cells: spines are longer and more numerous, features suggesting that
they are relatively immature.
Mice with transgenic mutation of the Fmr1 gene encoding the Fragile X
Mental Retardation Protein (FMRP) have similar alterations in spine morphology, and other abnormalities in
cortical fields including reduced levels of some ionotropic (i.e. AMPA) glutamate receptor subunits, and
hyper-responsive function of the group 1 metabotropic glutamate receptor 5 (mGluR5). Additionally, FX
mice have deficient Long Term Potentiation (LTP), the presumable cellular substrate of memory, and
learning deficits. Thus, this mutant is useful for testing hypotheses as to the consequences of lost FMRP
expression on spine shape/density and synaptic plasticity, and for testing manipulations intended to
counteract these consequences.
Studies show that AMPA treatment leads to a rounding and normalization
of spine morphology whereas treatment with brain derived neurotrophic factor (BDNF) leads to a reduction
in spine number and a shortening of surviving spines. Recent studies by Dr. Lauterborn demonstrate that
BDNF treatment restores hippocampal LTP in FX mice. These data suggest that
interventions that target AMPA-class receptors and augment neurotrophin availability, such as ampakine
treatment, could be of tremendous value for correcting abnormalities in dendritic spines and synaptic
function associated with mental retardation. Moreover, other work by Dr. Lauterborn demonstrates that
mGluR5 antagonism in combination with ampakine treatment elicits even greater elevations in BDNF
expression than does the ampakine alone, suggesting that a combined therapeutic approach may be more
beneficial for enhancing neurotrophism.
These studies are designed to test the hypothesis that in
the Fmr1 knockout (KO) mouse treatment with ampakines, which positively modulate AMPA- receptors
(AMPARs) and increase BDNF expression, will induce maturation-like changes in the morphologies of
cortical dendritic spines. Ampakines will be evaluated for effects on BDNF protein levels and spine
abnormalities, either alone or in combination with an mGluR5 antagonist. They will test whether co-treatment with ampakines and mGluR5 antagonists will induce greater increases
in BDNF protein content than with ampakines alone; studies will evaluate with two ampakines with different
half-lives. They will also test whether ampakine/mGluR5 antagonist co-treatment will
induce maturation-like changes in dendritic spines in adult Fmr1-KOs, and that the effects of combined
therapy will be greater than either drug alone. Studies will test if treatment influences spine shape and
number to normalize these features in a newly created FMR1-KO hybrid that expresses yellow fluorescent
protein in individual cortical neurons with labeling of dendritic spines.
by Julie Lauterborn, 6/2003
Studies in Fragile X mice reveal abnormalities in the shape and number of dendritic spines (where neurons receive input from other neurons), similar to the abnormalities seen in brain cells of humans with Fragile X. In addition, in the Fragile X mouse there is less glutamate receptor protein in the forebrain, suggesting that cognitive deficits in this syndrome may arise from impaired maturation of glutamate spine synapses.
Stimulation of AMPA-class glutamate receptors leads to a normalization of spine shape and stimulates brain neurons to synthesize increased levels of Brain-Derived Neurotrophic Factor (BDNF). BDNF is known to reduce spine number and length, as well as to increase AMPA receptor protein levels. These findings suggest that in Fragile X (and in the mouse model), increases in both AMPA receptor and BDNF signaling may effect changes in synapses that should ameliorate deficits in neurotransmission.
Recently we demonstrated that Ampakines, which increase AMPA receptor function, also increase BDNF expression in normal rodents. The data suggest that Ampakines could be useful therapeutics for dendritic spine abnormalities and cognitive deficits associated with Fragile X. We will test the hypotheses that (1) the regulation of AMPA receptor expression within the cell membrane is similar in Fragile X knockout and wildtype mice and (2) Ampakine facilitation of AMPA receptor function can be used to sustain increases in neuronal BDNF protein content in Fragile X knockout neurons.